Biofilm bacteria are estimated to cause two thirds of infections in modern clinical practice. In biofilms, microorganisms are protected from killing by innate host defenses and most available antimicrobial agents, culminating in the need for device removal in many device-associated infections (e.g., prosthetic joint infection). Given the failure of antimicrobics in the management of biofilm-associated device infections, a novel and innovative therapeutic and preventive non-antimicrobial approach is needed. Such a strategy would limit emergence of conventional antimicrobial resistance, as conventional antimicrobial agents would not be needed. Such a strategy would also limit toxicity associated with systemic antimicrobial agents. The preliminary in vitro studies described in our first submission demonstrated that electrical currents of 20 to 2000 <A substantially reduced established Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis biofilms, a phenomenon we termed the "electricidal effect" (Antimicrob Ag Chemother 2009;53:41). {Preliminary data generated with two new isolates each of P. aeruginosa, S. aureus, and S. epidermidis, three isolates each of Escherichia coli and Enterococcus faecalis, and single isolates of each of Streptococcus mutans species group and Candida albicans also demonstrate an electricidal effect.} We have shown that electrical current is active against S. epidermidis biofilms in a rabbit foreign body infection model (Antimicrob Ag Chemother 2009;53:4064). Notably, direct current has a precedent of being safely used in clinical practice (e.g., to accelerate fracture healing). We hypothesize that the electricidal effect is broadly active against a variety of bacterial and fungal biofilms (i.e., beyond those studied to date). We further hypothesize that electrical current will not only treat, but will also prevent biofilm formation, and that this strategy is safe. We will establish optimal in vitro and in vivo parameters to maximize the electricidal effect, and we will determine whether the observed killing of biofilm-associated P. aeruginosa, S. aureus, S. epidermidis, {E. coli, E. faecalis, S. mutans and C. albicans}, generalizes to other genera, species and strains of bacteria and fungi. {We will characterize adverse effects (if any) associated with delivery of electrical current in our animal model using functional (i.e., bone strength testing), whole organ (i.e., bone micro-computed tomography) and tissue (i.e., histomorphometry) assessments.} We will assess whether electrical current prevents bacterial adhesion to surfaces in vitro and in vivo. The mechanism that underlies this effect is unknown. We hypothesize that oxidative stress plays a role. {We have generated new preliminary data showing that, compared with wild-type bacteria, catalase-deficient bacteria have enhanced susceptibility to the electricidal effect, supporting our mechanistic hypothesis. If further studies do not support this hypothesis, we will evaluate detachment as a mechanism.} Results of this study are expected to provide a rationale and supporting data for the use of the electricidal effect for prevention and treatment of device-related bacterial infections in humans. This strategy has the potential to eliminate the need for device removal in human device-related infections. Not only will this approach be active against biofilms, but it will limit the emergence of resistance to conventional antimicrobial agents, resulting in less (futile) use of such drugs. PUBLIC HEALTH RELEVANCE: Microorganisms in biofilms cause a wide range of human infections, and biofilm microorganisms are resistant to most antibiotics used in clinical practice. {We have shown that electrical current is active against biofilms of six types of bacteria and one type of yeast in the laboratory and against one type of bacteria in an animal model.} We hypothesize that electrical current is active against a variety of bacteria and fungi in biofilms, which we plan to test in the laboratory and in an animal model. We further hypothesize that electrical current will not only treat, but will also prevent biofilm formation, which we will also test in the laboratory and in an animal model. We will examine the mechanism of the observed effect. We will establish optimal parameters to maximize the activity of electrical current against microbial biofilms. {And finally, we will characterize adverse effects associated with delivery of electrical current using our animal model.} Results of this study will provide a rationale and supporting data for use of electrical current for prevention and treatment of implant-associated infections (especially bone and joint infections) in humans. This new strategy would overcome the resistance to traditional antibiotics of microorganisms in biofilms.